Although mild traumatic brain injury (MTBI) affects over 1 million victims each year in the United States, it is generally ignored as a major health issue. However, this 'mild'form of injury induces persisting neurocognitive dysfunction in many of these patients, exacting an enormous emotional and financial toll on society. Despite the prevalence and impact of MTBI, little is known about potential anatomic or mechanistic substrates that are reflected by the clinical manifestations. We have assembled a unique multidisciplinary and multi-center team of investigators from the Center for Brain Injury and Repair (CBIR) at the University of Pennsylvania (Penn) and from Baylor College of Medicine in Houston to investigate two central hypotheses addressing clinical and mechanistic aspects of MTBI: 1) White matter injury, specifically diffuse axonal injury (DAI), is an important pathologic substrate of MTBI, and the extent and distribution of this injury will determine neurocognitive outcome, and 2) Axonal damage in MTBI is linked to mechanosensitive sodium channels;the persistent dysfunction of these channels will lead to short- and long-term axonal degeneration. To test these hypotheses of DAI in MTBI, we have organized the proposal into three projects (one clinical and two basic science) and two technical cores supporting neuroimaging and biomarker analyses. This Program represents a 'molecules to man'approach, using experimental models we have developed that span axon stretch injury in vitro to a mild head rotational acceleration TBI model in the pig. These models will be used in parallel investigations using non-invasive outcome measures of MTBI patients. This stepwise approach allows us to explore the evolving cellular and molecular effects of traumatic axon injury in a reduced model, confirm that these changes occur in vivo in the pig MTBI model, and extrapolate these findings to MTBI patients through comparison of non-invasive measures. Success of the proposed studies could lead to new diagnostic criteria to identify the pathologies and mechanisms in MTBI, predict long-term neurocognitive dysfunction after MTBI, and provide targets for new therapeutic interventions.